Molecular radiation biology research demonstrates that interactions of ionizing radiation with cells are not limited to DNA but induce complex responses involving existing signal transduction pathways. These cascades represent a highly interactive network that, through signals along and across defined pathways, contribute to overall cellular responses of cell survival and cell death. During the previous funding period, we characterized major pathways, along which signaling is initiated by membrane receptors, e.g., ERBB receptor Tyr kinases (RTKs), and additionally modified by other oncogenes. The major cascades characterized for radiation responses are the cytoprotective pathways inducing cell proliferation and enhanced repair through coordinated activation of RAS/MAPK and PI3K/AKT, and the stress cascade involving JNK/P38 with potential links to DNA damage recognition and repair. During the current funding period, we have identified molecular targets that are being processed for clinical testing. Therefore, a major focus of the renewal application will remain the identification and mechanistic characterization of molecular targets that will open new strateqies for the radiosensitization of tumor cells. The PPG renewal application is designed to take radiation signal transduction research to the next level that requires more complex studies on the regulatory interplay between different signaling pathways. The organization of the Program reflects this new direction by emphasizing interactions between similar components within the same cellular compartments. The translational power of these studies lies in the potential of combining multiple molecular targets for enhanced radiation cytotoxicity. The overall Program is comprised of three Projects. Project 1 focuses on interactions between receptor (ERBB, IGF1R) and non-receptor (SRC) Tyr kinases in the plasma membrane and their effects on cytoprotective pro-proliferative and anti-apoptotic pathways. This investigation feeds into studies examining interactions between K-RAS and H-RAS oncogenes and downstream cytoplasmic kinase cascades in Project 2 and their effects on cell cycle regulation, through P21, and P53, apoptosis and transcriptional control. Project 3 focuses on DNA damage recognition and repair, involving P53, ATM and DNA-PK and related signaling, including functional relationships with RTKs the other immediate radiation response system. The Projects are supported byViral Vector Core A for production of genetic reaqents, by Core B for execution of biological assays including in vivo validation assays for radiosensitization, and by Core C for provision of the administrative infrastructure.